PROJECT SUMMARY Candidate: I am a fellowship-trained retinal ophthalmologist with the long-term career goal of becoming an independent clinician scientist and nationally recognized leader in the field of age-related macular degeneration (AMD). My research agenda is focused on understanding the pathobiology of AMD and developing novel endpoints for clinical trials, biomarkers of disease progression, and therapeutic targets. I have a PhD in neuroscience and a longstanding interest in age-related degenerative diseases of the central nervous system and retina. My immediate career development goal in the current proposal is to characterize the monocytic cells the retina of AMD histopathology specimens and the association of monocytes with biomarkers of disease progression (imaging in autopsy eyes and clinical patients; visual fuction biomarkers in clinical patients). With a K23 mentored award, I would acquire additional didactic training and mentored research experience in in ocular pathology, microscopy, photonics, retinal imaging, clinical research, and responsible conduct of research. Environment: The mentorship and expertise of the advisory committee, the extensive resources of the Duke Eye Center and the Pathology department, and the significant institutional commitment will provide me with the support needed to transition successfully into an independent research career. Research: The focus of this grant is to investigate the hypothesis that infiltration of CD163+ macrophages into the outer retina in dry AMD will correlate with synaptic defects, possibly explaining some of the loss of visual function in these patients. We will assess whether infiltrating subretinal macrophages may be associated or may themselves be the structural features on retinal imaging known to be associated with disease progression. We will also evaluate whether high frequency of monocytes in the blood of patients will correlate with visual dysfunction and retinal imaging biomarkers, suggesting that retinal macrophages are derived from recruited circulating monocytes. In Specific Aim 1, using histopathological analysis of postmortem eyes with HRD, we will demonstrate that high frequency of outer retinal and subretinal macrophages is associated with markers of retinal damage (especially disrupted photoreceptor synapses) as compared to age-matched control eyes and with SD-OCT and SLO markers of pseudodrusen. In Specific Aim 2, using analysis of circulating monocytes by flow cytometry in subjects with dry AMD, we will show that the ratio of monocytes subtypes in the blood will correlate with the presence of imaging markers of disease progression and with visual function deficits of low luminance visual acuity, dark adaptation, cone contrast sensitivity and microperimetry testing. We will also isolate blood monocytes and perform analyses of gene expression to identify factors that may contribute to loss of vision. This body of work, which will constitute the basis of an R01 grant, will allow the discovery of new biomarkers of AMD progression and therapeutic targets involving macrophages.